As part of The Cancer Genome Atlas group characterizing head and neck cancer, we have identified components of the classical and alternative NF-kB, PI3K, and Notch pathways as candidate genetic drivers for aberrant NF-kB activation and defects in death signaling. We have reported that decreased TRAF3 contributes to aberrant activation of the alternative NF-kB pathway, which promotes migration of HNSCC. We have shown Notch1 mediates non-canonical activation of IKKalpha and NF-kB signaling in cutaneous squamous cell carcinoma stem cells. A clinical trial with PI3K-mTOR inhibitor rapamycin has completed accrual and been submitted for publication. Studies using a genome wide RNAi screen employing NF-kB reporter lines have identified potential drug targets promoting NF-kB activation, under investigation.